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JCI online ahead of print table of contents for March 18, 2014

Cardiac conduction altered by intragenic enhancer

Genome-wide association studies (GWAS) have determined a surprising link between dysfunctional cardiac conduction and variants within SCN10A, which encodes nociceptor-associated sodium-gated ion channel subunit NaV1.8. Follow-up functional studies targeting NaV1.8 revealed only a minor contribution to cardiac physiology; therefore, it was unclear how SCN10A mutations promoted the development of cardiac conduction disease. In this issue of the Journal of Clinical Investigation, the research groups of Vincent Christoffels, Marcelo Nobrega, Phil Barnett, and Ivan Moskowitz teamed up and have now revealed that a transcriptional enhancer within SCN10A is required for cardiac expression of SCN5A, encoding the sodium-gated ion channel subunit NaV1.5, which is critical for cardiac conduction. In humans, a variant in the enhancer within SCN10A was associated with slowed conduction, Brugada syndrome, and reduced SCN5A transcription. In the accompanying Commentary, David Park and Glenn Fishman of the New York School of Medicine discuss how this study highlights the importance of functional studies to distinguish between coding and non-coding functions of genomic regions identified by GWAS.

TITLE: A common genetic variant within SCN10A modulates cardiac SCN5A expression

AUTHOR CONTACT: Ivan Moskowitz
The University of Chicago, Chicago, IL, USA
Phone: 773 834 0462; Fax: 773 834 2132; E-mail:

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TITLE: Nav-igating through a complex landscape: SCN10A and cardiac conduction

NYU School of Medicine, New York, NY, USA
Phone: 212-263-3967; Fax: 212-263-3972; E-mail:

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Inflammatory feedback loop promotes colorectal cancer metastasis

Induction of the epithelial-mesenchymal transition (EMT) in cancer cells is associated with an increased capacity to invade into surrounding tissue and migrate to distant sites. The tumor-specific factors that drive EMT aren't completely understood; however, evidence implicates inflammation in this process. In this issue of the Journal of Clinical Investigation, a team led by Heiko Hermeking at Ludwigs-Maximilians University determined that exposure of human colorectal cancer cells to the proinflammatory cytokine IL-6 activates the oncogenic transcription factor STAT3, which represses the gene encoding microRNA-34a (miR-34a) and promotes mesenchymal phenotypes. The IL-6 receptor (IL-6R) was identified as a direct target of miR-34a, defining an IL-6R/STAT3/miR-34a feedback loop that promotes EMT, invasion, and metastasis. Activation of p53, which induces miR-34a, decreased IL-6-dependent invasion and migration via reduced IL-6R expression, while loss of miR-34a in a murine model of colitis-associated cancer resulted in enhanced. In an accompanying Commentary, Raghu Kalluri and colleagues of the University of Texas MD Anderson Cancer Center discuss the role of tumor microenvironment in promoting EMT and metastasis.

TITLE: IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis

AUTHOR CONTACT: Heiko Hermeking
Ludwigs-Maximilians University, Munich, , DEU
Phone: 011-49-89-2180-73685; Fax: 011-49-89-2180-73697; E-mail:

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ACCOMPANYING COMMENTARY TITLE: Microenvironment-dependent cues trigger miRNA-regulated feedback loop to facilitate the EMT/MET switch

University of Texas MD Anderson Cancer Center, Houston, TX, USA
Phone: 713-792-8586; E-mail:

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Insulin resistance in bone disrupts whole-body glucose homeostasis

Insulin signaling in osteoblasts mediates the activation of osteocalcin, which promotes insulin secretion in the pancreas and insulin sensitivity in other tissues. It is unknown if insulin resistance develops in bone in response to a high fat diet (HFD) and contributes to the disruption of glucose metabolism associated with the development of type 2 diabetes. In thie issue of the Journal of Clinical Investigation, Gerard Karsenty and colleagues of Columbia University determined that insulin resistance does develop in osteoblasts of mice fed a HFD and that this insulin resistance in bone cells contribute to the development of whole-body glucose intolerance through decreased circulation of active osteocalcin. Osteoblast-specific insulin resistance resulted, in part, from increased ubiquitination and degradation of the insulin receptor in response to saturated fatty acids. In the accompanying Commentary, Ryan Riddle and Thomas Clemens of Johns Hopkins University indicate that understanding the interplay between the skeletal system and whole-body metabolism will be beneficial for a wide range of metabolic diseases.

TITLE: Bone-specific insulin resistance disrupts whole-body glucose homeostasis via decreased osteocalcin activation

AUTHOR CONTACT: Gerard Karsenty
Columbia University, New York, NY, USA
Phone: 212 305 4011; E-mail:

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ACCOMPANYING COMMENTARY TITLE: Insulin, osteoblasts, and energy metabolism: why bone counts calories

AUTHOR CONTACT: Thomas Clemens
Center for Musculoskeletal Research, John Hopkins, Baltimore, MD, USA
Phone: 410.955.3245; E-mail:

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Pathogenic interactions between platelets and neutrophils are mediated by AKT2

Pathological interactions between blood cells promote thrombo-inflammatory disease and result in complications such as vaso-occlusion during atherothrombosis, inflammation, and ischemia. Activated platelets, leukocytes and endothelial cells all contribute to the development of vaso-occlusion: though how interactions between these cell types are regulated is poorly understood. In this issue of the Journal of Clinical Investigation, Jaehyung Cho and colleagues at the University of Illinois determined that the serine/threonine kinase AKT2 was required for heterotypic aggregation of activated platelets, neutrophils and endothelial cells during TNF-α-induced vascular inflammation. In neutrophils, AKT2 phosphorylation activated and resulted in membrane translocation of αMβ2 integrin, which promoted cell-cell attachment. Neutrophils and platelets from patients with sickle cell disease (SCD) had increased levels of AKT phosphorylation, and specific inhibition of AKT2 diminished aggregation of these patients' cells. In SCD mice, targeting AKT2 reduced platelet-neutrophil aggregation and improved blood flow rates. In a companion Commentary, Gregory Vercellotti and John Belcher of the University of Minnesota discuss the complicated etiology of SCD-associated vaso-occlusion.

TITLE: Neutrophil AKT2 regulates heterotypic cell-cell interactions during vascular inflammation

University of Illinois at Chicago, Chicago, IL, USA
Phone: 312-355-5923; E-mail:

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ACCOMPANYING COMMENTARY TITLE: Not simply misshapen red cells: multimolecular and cellular events in sickle vaso-occlusion

AUTHOR CONTACT: Gregory M Vercellotti
University of Minnesota, Minneapolis, MN, USA
Phone: 612 626 3757; Fax: 612 625 6919; E-mail:

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TITLE: Sympathetic activityassociated periodic repolarization dynamics predict mortality following myocardial infarction

Eberhard Karls University, Tbingen, Tbingen, , DEU
Phone: + 49.7071.29.82922; E-mail:

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TITLE: Human musclederived stem/progenitor cells promote functional murine peripheral nerve regeneration

University of Pittsburgh, Pittsburgh, PA, USA
Phone: 412-648-2798; Fax: 412-648-4066; E-mail:

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TITLE: Tumor endothelial marker 1specific DNA vaccination targets tumor vasculature

AUTHOR CONTACT: Andrea Facciabene
Ovarian Cancer Research Center, Philadelphya, PA, USA
Phone: 215-746-7071; Fax: 2155735129; E-mail:

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TITLE: Podocyte-specific RAP1GAP expression contributes to focal segmental glomerulosclerosisassociated glomerular injury

Mount Sinai School of Medicine, New York, NY, USA
Phone: 646 245-2294; Fax: 212 987-0389; E-mail:

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Contact: Corinne Williams
Journal of Clinical Investigation

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